Cancer cells are addicted to mutations that cause gain of function in oncogenes and loss of function in tumor suppressors, so that these cells are reliant on aberrant signaling pathways and transcription. Protein-protein and DNA-protein interactions that cause chromatin remodeling are another source of the deregulation of critical signaling and transcriptional regulators, altering epigenetic signatures and creating additional vulnerabilities. Owing to mutations in multiple epigenetic regulators in hematologic malignancies, cancer cells are highly addicted to altered transcription. These vulnerabilities have been targeted by several epigenetic drugs, including hypomethylating agents, but the idea of targeting bromodomain proteins has emerged relatively recently. Because bromodomain proteins recognize acetylated lysine on histones and recruit transcription complexes on the chromatin, targeting these proteins may serve as a strategy to target transcription, irrespective of the presence of epigenetic mutations. Here, we review the existing literature to explain the rationale of using bromodomain inhibitors in hematologic malignancies. We discuss the evolution of bromodomain inhibitors, with an in-depth evaluation of bromodomain and extraterminal domain (BET) proteins, the most prominent bromodomain family, and also highlight the prospect of targeting non-BET proteins. In the later sections, we comment on the combinatorial targeting of BET proteins to overcome the effects of multiple signaling pathways. Finally, we emphasize the newer concepts, such as dual-kinase inhibition and selective bromodomain targeting, and technologies, such as protein degradation, that are expected to influence the future generation of bromodomain inhibitors.
